bims-senagi 2022-05-01 papers

bims-senagi

Biomed News

on Senescence and aging

Issue of 2022–05–01
thirteen papers selected by
Maria Grazia Vizioli, Mayo Clinic

Senolytics Cocktail Dasatinib and Quercetin Alleviate Human Umbilical Vein Endothelial Cell Senescence via the TRAF6-MAPK-NF-κB Axis in a YTHDF2-Dependent Manner.
Piperine: An Anticancer and Senostatic Drug.
The role of senescence in cellular plasticity: Lessons from regeneration and development and implications for age-related diseases.
Characterization of radiation-induced micronuclei associated with premature senescence, and their selective removal by senolytic drug, ABT-263.
Reducing ER stress with chaperone therapy reverses sleep fragmentation and cognitive decline in aged mice.
Autophagy in age-related macular degeneration.
Assessment of cell cycle regulators in human peripheral blood cells as markers of cellular senescence.
Single-cell atlas of the aging mouse colon.
Loss of SIRT1 inhibits hematopoietic stem cell aging and age-dependent mixed phenotype acute leukemia.
Accumulation of γδ T cells in visceral fat with aging promotes chronic inflammation.
The aging epigenome.
Cytoplasmic PARP1 links the genome instability to the inhibition of antiviral immunity through PARylating cGAS.
Circulating cell-free mtDNA release is associated with the activation of cGAS-STING pathway and inflammation in mitochondrial diseases.

Gerontology. 2022 Apr 25. 1-15

Senolytics Cocktail Dasatinib and Quercetin Alleviate Human Umbilical Vein Endothelial Cell Senescence via the TRAF6-MAPK-NF-κB Axis in a YTHDF2-Dependent Manner.

Ting Fan, Yi Du, Mingwan Zhang, Austin Rui Zhu, Jianjun Zhang.

   INTRODUCTION: Senescent cells play a key role in the initiation and development of various age-related diseases. Human umbilical vein endothelial cells (HUVECs) senescence is closely associated with age-related cardiovascular diseases. Accumulating evidence has demonstrated that senolytics, the combination of dasatinib and quercetin (D+Q), could selectively eliminate senescent cells. N6-methyladenosine (m6A), the most abundant internal transcript modification, greatly influences RNA metabolism and modulates gene expression. We aimed to investigate whether RNA m6A functions in lipopolysaccharide (LPS)-induced HUVECs senescence and D+Q suppress HUVECs senescence by regulating RNA m6A.
METHODS: Senescence-associated β-galactosidase activity, western blot, and real-time quantitative polymerase chain reaction were performed to demonstrate that D+Q suppress HUVECs senescence. Methylated RNA immunoprecipitation (MeRIP)-qPCR assay and RIP-qPCR confirmed that RNA m6A plays a key role in the suppression of HUVECs senescence by D+Q. Chromatin immunoprecipitation and mRNA stability assay were carried out to prove that D+Q alleviate HUVECs senescence in a YTHDF2-dependent manner.
RESULTS: Here, we demonstrate that D+Q alleviate LPS-induced senescence in HUVECs via inhibiting autocrine and paracrine of the senescence-associated secretory phenotype (SASP). We further confirm that D+Q alleviate HUVECs senescence via the TNF receptor-associated factor 6 (TRAF6)-MAPK pathway. Mechanically, this study validates that D+Q suppress SASP by upregulating m6A reader YTHDF2. Besides, YTHDF2 regulates the stability of MAP2K4 and MAP4K4 mRNAs.
CONCLUSION: Collectively, we first identified that D+Q alleviate LPS-induced senescence in HUVECs via the TRAF6-MAPK-NF-κB axis in a YTHDF2-dependent manner, providing novel ideas for clinical treatment of age-related cardiovascular diseases.

Keywords:  Dasatinib; Inflammation; Quercetin; Senescence; Senolytics; YTHDF2

DOI:  https://doi.org/10.1159/000522656
Front Biosci (Landmark Ed). 2022 Apr 20. 27(4): 137

Piperine: An Anticancer and Senostatic Drug.

Jae Sung Lim, Da Young Lee, Ju Hyeon Lim, Won Keun Oh, Jun Tae Park, Sang Chul Park, Kyung A Cho.

   BACKGROUND: Cancer is a representative geriatric disease closely related to senescent cells and cell aging in tissues. Senescent cells that surround cancer tissues reduce the effects of various cancer treatments and induce cancer recurrence through senescence-associated secretory phenotype (SASP) secretion. Thus, for good therapeutic effect, candidate drugs should be selective for both cancer and senescent cells. In this study, we investigated the selective effect of piperine as a potential senostatic agent as well as an anticancer drug.
METHODS: The effect of piperine on cytotoxicity and cell proliferation was tested by lactate dehydrogenase (LDH) or water-soluble tetrazolium salt (WST) assay. The levels of p16INK4a and p21, mitogen-activated protein kinases (MAPKs), and mammalian target of rapamycin (mTOR) were analyzed by Western blot analysis. The rejuvenation effects of piperine on the senescent cells were investigated by senescence-associated beta-galactosidase (SA-β-Gal) stain, mitochondria membrane potential (MMP) and reactive oxygen species (ROS) levels, and senescence-associated secretory phenotype (SASP) secretion after treatment with piperine in senescent cells.
RESULTS: While piperine induced high cytotoxicity in various cancer cell lines, it led to proliferating of premature senescent cells similar with nicotinamide (NA), which is known as a rejuvenating drug of senescent cells. Piperine differently affected cancer cells and premature senescent cells due to the different responses of intracellular signaling pathways and also reversed premature senescence phenotypes and modulated SASP secretion in premature senescent cells.
CONCLUSIONS: From these results, we propose piperine as an effective cancer treatment that can simultaneously induce senostatic effects and the removal of cancer cells, not as an adjuvant to the existing senostatics for cancer treatment.

Keywords:  anticancer; human diploid fibroblasts; piperine; senescence; senescence-associated secretory phenotype; senostatic

DOI:  https://doi.org/10.31083/j.fbl2704137
Dev Cell. 2022 Apr 18. pii: S1534-5807(22)00245-3. [Epub ahead of print]

The role of senescence in cellular plasticity: Lessons from regeneration and development and implications for age-related diseases.

Nadja Anneliese Ruth Ring, Karla Valdivieso, Johannes Grillari, Heinz Redl, Mikolaj Ogrodnik.

  Senescence is a cellular state which involves cell cycle arrest and a proinflammatory phenotype, and it has traditionally been associated with cellular and organismal aging. However, increasing evidence suggests key roles in tissue growth and regrowth, especially during development and regeneration. Conversely, cellular plasticity-the capacity of cells to undergo identity change, including differentiation and dedifferentiation-is associated with development and regeneration but is now being investigated in the context of age-related diseases such as Alzheimer disease. Here, we discuss the paradox of the role for cellular senescence in cellular plasticity: senescence can act as a cell-autonomous barrier and a paracrine driver of plasticity. We provide a conceptual framework for integrating recent data and use the interplay between cellular senescence and plasticity to provide insight into age-related diseases. Finally, we argue that age-related diseases can be better deciphered when senescence is recognized as a core mechanism of regeneration and development.

Keywords:  aging; cell plasticity; cellular senescence; differentiation; regeneration; wound healing

DOI:  https://doi.org/10.1016/j.devcel.2022.04.005
Mutat Res Genet Toxicol Environ Mutagen. 2022 Apr-May;876-877:pii: S1383-5718(22)00009-2. [Epub ahead of print]876-877 503448

Characterization of radiation-induced micronuclei associated with premature senescence, and their selective removal by senolytic drug, ABT-263.

Keiji Suzuki, Kasumi Kawamura, Risa Ujiie, Takahumi Nakayama, Norisato Mitsutake.

  Radiotherapy is well-recognized as an efficient non-invasive remedy for cancer treatment. Since 10 Gy, a weekly total dose for conventional radiotherapy, was proven to create unreparable and residual DNA double-strand breaks (DSBs), they were found to give rise to mitotic failure, such as mitotic catastrophe, which resulted in multiple micronuclei associated with premature senescence. We demonstrated that pulverization of micronuclear DNA was caspase-dependent and triggered not ATM-dependent but DNA-PK-dependent DNA damage response, including phosphorylation of histone H2AX. Pulverization of micronuclear DNA and senescence-associated secretory phenotype (SASP) worsen tumor microenvironment after radiotherapy, so that senolytic drug was applied to eliminate senescent cancer cells. Prematurely senescent cancer cells with micronuclei caused by 10 Gy of γ-irradiation were subjected to 5 μM of ABT-263, a Bcl-2 family inhibitor, and selective cancer cell death by apoptosis was observed, while ABT-263 had little effect on growing cancer cells. Western blot analysis showed augmented expression of both apoptotic and anti-apoptotic proteins in senescent cells, indicating that increased apoptotic factors are essential for selective apoptotic cell death in combination with ABT-263. Our results suggested that selective elimination of senescent cells alleviates SASP and micronuclei-mediated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) activation, both of which lead to unfavorable adverse effects caused by radiotherapy.

Keywords:  Apoptosis; Cancer; Micronucleus; Radiation; Senescence; Senolysis

DOI:  https://doi.org/10.1016/j.mrgentox.2022.503448
Aging Cell. 2022 Apr 30. e13598

Reducing ER stress with chaperone therapy reverses sleep fragmentation and cognitive decline in aged mice.

Jennifer M Hafycz, Ewa Strus, Nirinjini Naidoo.

  As the aging population grows, the need to understand age-related changes in health is vital. Two prominent behavioral changes that occur with age are disrupted sleep and impaired cognition. Sleep disruptions lead to perturbations in proteostasis and endoplasmic reticulum (ER) stress in mice. Further, consolidated sleep and protein synthesis are necessary for memory formation. With age, the molecular mechanisms that relieve cellular stress and ensure proper protein folding become less efficient. It is unclear if a causal relationship links proteostasis, sleep quality, and cognition in aging. Here, we used a mouse model of aging to determine if supplementing chaperone levels reduces ER stress and improves sleep quality and memory. We administered the chemical chaperone 4-phenyl butyrate (PBA) to aged and young mice, and monitored sleep and cognitive behavior. We found that chaperone treatment consolidates sleep and wake, and improves learning in aged mice. These data correlate with reduced ER stress in the cortex and hippocampus of aged mice. Chaperone treatment increased p-CREB, which is involved in memory formation and synaptic plasticity, in hippocampi of chaperone-treated aged mice. Hippocampal overexpression of the endogenous chaperone, binding immunoglobulin protein (BiP), improved cognition, reduced ER stress, and increased p-CREB in aged mice, suggesting that supplementing BiP levels are sufficient to restore some cognitive function. Together, these results indicate that restoring proteostasis improves sleep and cognition in a wild-type mouse model of aging. The implications of these results could have an impact on the development of therapies to improve health span across the aging population.

Keywords:  aging; anti-aging; behavior; molecular biology of aging; mouse models; neuroscience

DOI:  https://doi.org/10.1111/acel.13598
Autophagy. 2022 Apr 25.

Autophagy in age-related macular degeneration.

Kai Kaarniranta, Janusz Blasiak, Paloma Liton, Michael Boulton, Daniel J Klionsky, Debasish Sinha.

  Age-related macular degeneration (AMD) is the leading cause of visual impairment in the aging population with limited understanding of its pathogenesis and a lack of effective treatment. The progression of AMD is initially characterized by atrophic alterations in the retinal pigment epithelium, as well as the formation of lysosomal lipofuscin and extracellular drusen deposits. Damage caused by chronic oxidative stress, protein aggregation and inflammatory processes may lead to geographic atrophy and/or choroidal neovascularization and fibrosis. The role of macroautophagy/autophagy in AMD pathology is steadily emerging. This review describes selective and secretory autophagy and their role in drusen biogenesis, senescence-associated secretory phenotype, inflammation and epithelial-mesenchymal transition in the pathogenesis of AMD.

Keywords:  autophagy; immune response; lysosome; retina; stress; vision

DOI:  https://doi.org/10.1080/15548627.2022.2069437
Ageing Res Rev. 2022 Apr 20. pii: S1568-1637(22)00076-9. [Epub ahead of print]78 101634

Assessment of cell cycle regulators in human peripheral blood cells as markers of cellular senescence.

Lihuan Guan, Karen C Crasta, Andrea B Maier.

  Cellular senescence has gained increasing interest during recent years, particularly due to causal involvement in the aging process corroborated by multiple experimental findings. Indeed, cellular senescence considered to be one of the hallmarks of aging, is defined as a stable growth arrest predominantly mediated by cell cycle regulators p53, p21 and p16. Senescent cells have frequently been studied in the peripheral blood of humans due to its accessibility. This review summarizes ex vivo studies describing cell cycle regulators as markers of senescence in human peripheral blood cells, along with detection methodologies and associative studies examining demographic and clinical characteristics. The utility of techniques such as the quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), microarray, RNA sequencing and nCounter technologies for detection at the transcriptional level, along with Western blotting, enzyme-linked immunosorbent assay and flow cytometry at the translational level, will be brought up at salient points throughout this review. Notably, housekeeping genes or proteins serving as controls such as GAPDH and β-Actin, were found not to be stably expressed in some contexts. As such, optimization and validation of such genes during experimental design were recommended. In addition, the expression of cell cycle regulators was found to vary not only between different types of blood cells such as T cells and B cells but also between stages of cellular differentiation such as naïve T cells and highly differentiated T cells. On the other hand, the associations of the presence of cell cycle regulators with demographics (age, gender, ethnicity, and socioeconomic status), clinical characteristics (body mass index, specific diseases, disease-related parameters) and lifestyle vary in groups of participants. One envisions that increased understanding and insights into the assessment of cell cycle regulators as markers of senescence in human peripheral blood cells will help inform prognostication and clinical intervention in elderly individuals.

Keywords:  Ageing; Blood; Cellular senescence; Cyclin-dependent kinase inhibitor p21; p16; p53

DOI:  https://doi.org/10.1016/j.arr.2022.101634
iScience. 2022 May 20. 25(5): 104202

Single-cell atlas of the aging mouse colon.

Dovydas Širvinskas, Omid Omrani, Jing Lu, Mahdi Rasa, Anna Krepelova, Lisa Adam, Sandra Kaeppel, Felix Sommer, Francesco Neri.

  We performed massive single-cell sequencing in the aging mouse colonic epithelium and immune cells. We identified novel compartment-specific markers as well as dramatic aging-associated changes in cell composition and signaling pathways, including a shift from absorptive to secretory epithelial cells, depletion of naive lymphocytes, and induction of eIF2 signaling. Colon cancer is one of the leading causes of death within the western world, incidence of which increases with age. The colonic epithelium is a rapidly renewing tissue, tasked with water and nutrient absorption, as well as hosting intestinal microbes. The colonic submucosa is populated with immune cells interacting with and regulating the epithelial cells. However, it is unknown whether compartment-specific changes occur during aging and what impact this would cause. We show that both epithelial and immune cells differ significantly between colonic compartments and experience significant age-related changes in mice. We found a shift in the absorptive-secretory cell balance, possibly linked to age-associated intestinal disturbances, such as malabsorption. We demonstrate marked changes in aging immune cells: population shifts and interactions with epithelial cells, linking cytokines (Ifn-γ, Il1B) with the aging of colonic epithelium. Our results provide new insights into the normal and age-associated states of the colon.

Keywords:  Cell biology; Immunology; Omics; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2022.104202
Commun Biol. 2022 Apr 28. 5(1): 396

Loss of SIRT1 inhibits hematopoietic stem cell aging and age-dependent mixed phenotype acute leukemia.

Zhiqiang Wang, Chunxiao Zhang, Charles David Warden, Zheng Liu, Yate-Ching Yuan, Chao Guo, Charles Wang, Jinhui Wang, Xiwei Wu, Richard Ermel, Steven L Vonderfecht, Xiuli Wang, Christine Brown, Stephen Forman, Yaling Yang, M James You, WenYong Chen.

Aging of hematopoietic stem cells (HSCs) is linked to various blood disorders and malignancies. SIRT1 has been implicated in healthy aging, but its role in HSC aging is poorly understood. Surprisingly, we found that Sirt1 knockout improved the maintenance of quiescence of aging HSCs and their functionality as well as mouse survival in serial bone marrow transplantation (BMT) recipients. The majority of secondary and tertiary BMT recipients of aging wild type donor cells developed B/myeloid mixed phenotype acute leukemia (MPAL), which was markedly inhibited by Sirt1 knockout. SIRT1 inhibition also reduced the growth and survival of human B/myeloid MPAL cells. Sirt1 knockout suppressed global gene activation in old HSCs, prominently the genes regulating protein synthesis and oxidative metabolism, which may involve multiple downstream transcriptional factors. Our results demonstrate an unexpected role of SIRT1 in promoting HSC aging and age-dependent MPAL and suggest SIRT1 may be a new therapeutic target for modulating functions of aging HSCs and treatment of MPAL.

DOI: https://doi.org/10.1038/s42003-022-03340-w
Geroscience. 2022 Apr 28.

Accumulation of γδ T cells in visceral fat with aging promotes chronic inflammation.

Maria E C Bruno, Sujata Mukherjee, Whitney L Powell, Stephanie F Mori, Franklyn K Wallace, Beverly K Balasuriya, Leon C Su, Arnold J Stromberg, Donald A Cohen, Marlene E Starr.

  Adipose tissue dysfunction is strongly linked to the development of chronic inflammation and cardiometabolic disorders in aging. While much attention has been given to the role of resident adipose tissue immune cells in the disruption of homeostasis in obesity, age-specific effects remain understudied. Here, we identified and characterized a population of γδ T cells, which show unique age-dependent accumulation in the visceral adipose tissue (VAT) of both mice and humans. Diet-induced obesity likewise increased γδ T cell numbers; however, the effect was greater in the aged where the increase was independent of fat mass. γδ T cells in VAT express a tissue-resident memory T cell phenotype (CD44hiCD62LlowCD69+) and are predominantly IL-17A-producing cells. Transcriptome analyses of immunomagnetically purified γδ T cells identified significant age-associated differences in expression of genes related to inflammation, immune cell composition, and adipocyte differentiation, suggesting age-dependent qualitative changes in addition to the quantitative increase. Genetic deficiency of γδ T cells in old age improved the metabolic phenotype, characterized by increased respiratory exchange ratio, and lowered levels of IL-6 both systemically and locally in VAT. Decreased IL-6 was predominantly due to reduced production by non-immune stromal cells, primarily preadipocytes, and adipose-derived stem cells. Collectively, these findings suggest that an age-dependent increase of tissue-resident γδ T cells in VAT contributes to local and systemic chronic inflammation and metabolic dysfunction in aging.

Keywords:  Adipose tissue; Aging; Chronic inflammation; Gamma delta T cells; Obesity

DOI:  https://doi.org/10.1007/s11357-022-00572-w
Elife. 2022 Apr 28. pii: e78693. [Epub ahead of print]11

The aging epigenome.

Brandon L Pierce.

  A new approach helps to assess the impact of accelerated epigenetic aging on the risk of cancer.

Keywords:  DNA methylation; Mendelian randomization; cancer; epidemiology; epigenetic age acceleration; epigenetic clocks; genetics; genomics; human; medicine

DOI:  https://doi.org/10.7554/eLife.78693
Mol Cell. 2022 Apr 14. pii: S1097-2765(22)00290-8. [Epub ahead of print]

Cytoplasmic PARP1 links the genome instability to the inhibition of antiviral immunity through PARylating cGAS.

Fei Wang, Mengmeng Zhao, Boran Chang, Yilong Zhou, Xiangyang Wu, Mingtong Ma, Siyu Liu, Yajuan Cao, Mengge Zheng, Yifang Dang, Junfang Xu, Li Chen, Tianhao Liu, Fen Tang, Yefei Ren, Zhu Xu, Zhiyong Mao, Kai Huang, Minhua Luo, Jingsong Li, Haipeng Liu, Baoxue Ge.

  Virus infection modulates both host immunity and host genomic stability. Poly(ADP-ribose) polymerase 1 (PARP1) is a key nuclear sensor of DNA damage, which maintains genomic integrity, and the successful application of PARP1 inhibitors for clinical anti-cancer therapy has lasted for decades. However, precisely how PARP1 gains access to cytoplasm and regulates antiviral immunity remains unknown. Here, we report that DNA virus induces a reactive nitrogen species (RNS)-dependent DNA damage and activates DNA-dependent protein kinase (DNA-PK). Activated DNA-PK phosphorylates PARP1 on Thr594, thus facilitating the cytoplasmic translocation of PARP1 to inhibit the antiviral immunity both in vitro and in vivo. Mechanistically, cytoplasmic PARP1 interacts with and directly PARylates cyclic GMP-AMP synthase (cGAS) on Asp191 to inhibit its DNA-binding ability. Together, our findings uncover an essential role of PARP1 in linking virus-induced genome instability with inhibition of host immunity, which is of relevance to cancer, autoinflammation, and other diseases.

Keywords:  DNA damage response; DNA-dependent protein kinase; PARylation; antiviral immunity; cyclic GMP-AMP synthase; inducible nitric oxide synthase; poly(ADP-ribose) polymerase 1; type I interferon

DOI:  https://doi.org/10.1016/j.molcel.2022.03.034
J Neurol. 2022 Apr 29.

Circulating cell-free mtDNA release is associated with the activation of cGAS-STING pathway and inflammation in mitochondrial diseases.

Xutong Zhao, Meng Yu, Yawen Zhao, Yiming Zheng, Lingchao Meng, Kang Du, Zhiying Xie, He Lv, Wei Zhang, Jing Liu, Qingqing Wang, Yun Yuan, Zhaoxia Wang, Jianwen Deng.

   BACKGROUND: There is increasing evidence for the role of inflammation in the pathogenesis of mitochondrial diseases (MDs). However, the mechanisms underlying mutation-induced inflammation in MD remain elusive. Our previous study suggested that mitophagy is impaired in the skeletal muscle of those with MD, likely causing mitochondrial DNA (mtDNA) release and thereby triggering inflammation. We here aimed to decipher the role of the cGAS-STING pathway in inflammatory process in MDs.
METHODS: We investigated the levels of circulating cell-free mtDNA (ccf-mtDNA) in the serum of 104 patients with MDs. Immunofluorescence was performed in skeletal muscles in MDs and control. Biochemical analysis of muscle biopsies was conducted with western blot to detect cGAS, STING, TBK1, IRF3 and phosphorylated IRF3 (p-IRF3). RT-qPCR was performed to detect the downstream genes of type I interferon in skeletal muscles. Furthermore, a protein microarray was used to examine the cytokine levels in the serum of patients with MDs.
RESULTS: We found that ccf-mtDNA levels were significantly increased in those with MDs compared to the controls. Consistently, the immunofluorescent results showed that cytosolic dsDNA levels were increased in the muscle samples of MD patients. Biochemical analysis of muscle biopsies showed that cGAS, IRF3, and TBK1 protein levels were significantly increased in those with MDs, indicating that there was activation of the cGAS-STING pathway. RT-qPCR showed that downstream genes of type I interferon were upregulated in muscle samples of MDs. Protein microarray results showed that a total of six cytokines associated with the cGAS-STING pathway were significantly increased in MD patients (fold change > 1.2, p value < 0.05).
CONCLUSIONS: These findings suggest that increases in ccf-mtDNA levels is associated with the activation of the cGAS-STING pathway, thereby triggering inflammation in MDs.

Keywords:  Ccf-mtDNA; Inflammation; Mitochondrial diseases; cGAS-STING pathway

DOI:  https://doi.org/10.1007/s00415-022-11146-3